Nathan B. Bennett*, Laurie B. Mlinar, Eric G. Moschetta, Ryan G. Ellis, Ryan Chung, Onkar Manjrekar, Michael Rasmussen, Laura A. McKee, Mark A. Servos, Justin A. Simanis, Bradley D. Gates, Xiaoqiang Shen, Dennie S. Welch and Zhe Wang,
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引用次数: 0
摘要
制备 ABBV-154 药物连接剂的最后一步是对三个叔丁基保护基团进行整体酸性脱保护,这一过程需要经过多个中间体,并因产生非对映异构体的缩醛外延而变得复杂。这种复杂的反应最初是在间歇式装置中进行优化的,但规模问题促使我们开发了一种带有撞击喷射混合元件的流动工艺。最初的研究利用市场上出售的 Y 型混合器进行小规模实验,但很难避免混合器的堵塞。为了避免这一问题并缩小工厂规模喷流的几何尺寸,实验室开发了一种三维(3D)打印的 Y 型混合器撞击喷流。在生产环境中执行公斤级的撞击过程,保持了所需的非对映选择性,并通过反相色谱法纯化了药物连接剂。本文讨论了为确保成功放大对混合敏感的反应而检查的关键参数,与批量工艺相比,该反应在流动过程中表现出更优越的选择性。
Use of Impinging Jet to Improve Scalability in the Preparation of the ABBV-154 Drug-Linker
The final step in the preparation of the ABBV-154 drug-linker is a global acidic deprotection of three tert-butyl protecting groups that proceeds through several intermediates and is complicated by acetal epimerization, which generates an undesired diastereomer. This complex reaction was initially optimized in a batch setup, but scaling issues prompted the development of a flow process with an impinging jet mixing element. Initial studies utilized commercially available Y-mixers for small-scale experiments; however, clogging of the mixer was difficult to avoid. A three-dimensional (3D) printed Y-mixer impinging jet was created for lab development to avoid this issue and scale down the geometry of the plant-scale jet. The impinging process was executed in the manufacturing environment at kilogram scale, maintaining the desired diastereoselectivity, and reversed-phase chromatography enabled purification of the drug-linker. This paper discusses the key parameters examined to ensure successful scale-up of a mixing-sensitive reaction that demonstrated superior selectivity in flow compared to the batch process.
期刊介绍:
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools,process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.